The purpose of this study is to prepare and evaluate a new class of nonsteroidal antiestrogens which are superior to those currently used in the treatment of breast cancer. Presently, no antiestrogens are available which are devoid of estrogenic (uterotropic) activity. Data presented in this proposal indicate that a lead compound, Analog II, is devoid of uterotropic activity in mouse uteri, which is unlike other antiestrogens in existence. Analog II has been found to be either as effective or more effective than tamoxifen (a clinically used antiestrogen with uterotropic activity) in the treatment of established tumors and the prevention of tumorigenesis in the 7,12-dimethylbenz( )anthracene (DMBA)-induced rat mammary tumor model. Based on these findings with Analog II and the steric features in existing antiestrogens, a new class of antiestrogens is proposed. Consequently, these new analogs, when prepared, will be prepared, will be examined in assay systems for their estrogenic, antiestrogenic and effect on gonadotropin secretion in vivo and receptor binding activity in vitro. All compounds will be evaluated further in a MCF-7 human breast cancer cell line to assess antitumor activity. Active members of this novel class of antiestrogens which lack estrogen agonist activity in humans would significantly improve the treatment of estrogen-dependent tumors in patients with breast cancer. Also, those compounds which have very few side effects would be useful prophylactically in preventing the genesis of estrogen-dependent tumors in women who are in the high risk category.